2-(di - (beta-hydroxy-lower alkyl)amino)-4,7-di - (heterocyclic amino) - 6 - phenyl-pteridines

ABSTRACT

COMPOUNDS OF THE FORMULA   2-(CH3-CH(-OH)-CH2-N(-R4)-),4-R2,6-(C6H5-),7-R3-PTERIDINE   WHEREIN   R2 IS MORPHOLINO OR 2&#39;&#39;-METHYL-MORPHOLINO, R3 IS PYRROLIDINO, PIPERIDINO, 3&#39;&#39;-HYDROXY-PIPERIDINO MORPHOLINO, OR 2&#39;&#39;-METHYLMORPHOLINO, AND R4 IS B-HYDROXY-ETHYL OR B-HYDROXY-N-PROPYL, USEFUL AS CORONARY DILATORS IN WARM-BLOODED ANIMALS.

United States Patent Int. (:1. 067a 57/28 US. Cl. 260247.5 11 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula wherein R is morpholino or 2'-methyl-morpholino,

R is pyrrolidino, piperidino, 3'-hydroxy-piperidino morpholino, or 2-methylmorpholino, and

R is ,B-hydroxy-ethyl or B-hydroxy-n-propyl, useful as coronary dilators in warm-blooded animals.

US. Pat. 2,940,972 discloses 2,4,6,7-tetra-substituted pteridines, where one of the substituents is a nitrogencontaining heterocyclic ring, two of the other substituents are substituted or unsubstituted amino or a nitrogencontaining heterocyclic ring, and the fourth substituent is substituted or unsubstituted amino, a nitrogen-containing heterocyclic'ring, hydrogen, halogen, alkyl, aralkyl, aryl, substituted or unsubstituted hydroxyl, or substituted or unsubstituted mercapto. These compounds are disclosed to exhibit coronary-dilating, antipyretic, analgesic and sedative activties.

This invention relates to novel 2,4,6,7-tetra-substituted pteridines as well as to various methods of preparing these compounds.

More particularly, the present invention relates to tetrasubstituted pteridines of the formula wherein Ar is phenyl, halo-phenyl, nitro-phenyl, hydroxy-phenyl,

lower alkyl-phenyl or lower alkoxy-phenyl,

R is di-lower alkyl-amino, alkyl-cycloalkyl-amino or alkyl-aralkyl-amino, each-having one or more hydroxyl substituents attached to the hydrocarbon moiety, and

R and R are each pyrrolidino, hydroxy-pyrrolidino, lower alkyl-pyrrolidino, piperidino, hydroxy-piperidino, lower alkyl-piperadino, piperazino, hydroxy-piperazino, lower alkyl-piperazino, morpholino or lower alkylmorpholino.

The compounds according to the present invention may be prepared by a number of different methods involving well known chemical principles, among which the following have proved to be particularly convenient and efficient:

3,557,106 Patented Jan. 19, 1971 "ice Method A By reacting a compound of the formula RF T Z. \AN

Method B By reacting a compound of the formula wherein Ar, R and R have the same meanings as in Formula I and Z is halogen, substituted hydroxyl or substituted mercapto, with an amine of the formula R H wherein R has the same meanings as in Formula I.

The reactions of methods A and B are carried out at a temperature between room temperature and 220 C., if desired in the presence of an acid-binding agent and of an inert solvent. The selection of the proper reaction temperature depends mainly upon the nature of substituents Z Z and Z as well as upon the reactivity of the amines R H, R H and R H. If Z Z or Z are halogen, only moderately elevated reaction temperatures are required to replace them by R R or R respectively. On the other hand, if Z Z or Z are substituted hydroxyl or substituted mercapto, the replacement reaction requires higher reaction temperatures; in some instances it is advantageous to add a reaction accelerator, preferably a copper salt or a. salt formed by the amine reaction component with an acid, or to perform the reaction in a closed vessel.

In those cases where Z Z and Z are substituted hydroxyl or substituted mercapto, the substituents may be lower alkyl, aralkyl or aryl.

The solvent medium for the reaction may be any desired inert organic solvent, such as acetone, benzene, dioxane or dimethylformamide.

The acid-binding agent may be an inorganic or tertiary organic base, such as an alkali metal hydroxide, an alkali metal carbonate or a trialkylamine; or also one or more of the amine reaction components R H, R H and R H, provided they are present in suflicient excess over and above the amount stoichiometrically required to react with the pteridine compound II or III. If present insuflicient quantity, the amine reaction components may also serve as the solvent medium for the reaction.

If method A is used to replace Z and Z with R and R which are identical to each other, the reaction mixture must contain at least two mols of the amine reactant per mol of pteridine compound II. On the other hand, if method A is used to replace Z and Z with R and R which are different from each other, the reaction may be performed stepwise as follows: If Z and 2;, are identical, for instance, if both are halogen, Z is replaced first by R and then in a second reaction step Z is replaced by R on the other hand, if Z and Z are not identical, for instance, if one is halogen and the other is substituted hydroxyl or substituted mercapto, the halogen is replaced first, as a rule.

The pteridine compounds II and III used as starting materials in methods A and B may themselves be prepared by the process described in U.S. Patent 2,940,972. Thus, a compound of the Formula II may, for instance, be obtained by reacting an analogous 6-aryl-2,4,7-trichloro-pteridine stepwise, first with an alkali metal mercaptide and then with a hydroxyalkyl-amine; and a compound of the Formula III may, for instance, be obtained by reacting a 4,7-dichloro-2-alkylmarcapto-6-aryl-pteriidine with compounds of the formula R H and R H, as defined above. In this manner, the following previously unknown starting compounds were prepared:

2 (N-ethanol-isopropanolamino)-7-chloro-4-(2-methyl-morpholino)-6-phenyl-pteridine, M.P. 9498 C.;

7 chloro-2-diisopropanolamino-4-(2'-methyl-morpholino)-6-phenyl-pteridine, M.P. 97103 C.;

2 (N-ethanol-diisopropanolamino)-4-(2'-methyl-morpholino)-7-phenoxy-6-phenyl-pteridine; and

2 diisopropanolamino 4 (2'-methyl-morpholino)-7- phenoxy-6-phenyl-pteridine.

The following examples further illustrate the instant invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the present invention is not limited solely to the particular examples given below.

EXAMPLE 1 Preparation of 2-diisopropanolamino-4,7-dimorpholino-6- phenyl-pteridine by Method A (a) 9.2 gm. (0.02 mol) of 2-diisopropanolamino-4- morpholine-7-chloro-6-phenyl-pteridine, M.P. 177-l79 C. (prepared by heating 2,7-dichloro-4-morpholino-6-phenylpteridine with diisopropanolamine in dioxane for about five hours), were admixed with cc. of morpholine, and the mixture was refluxed for thirty minutes. Thereafter, While it was still hot, the dark-colored reaction solution was poured into about 500 cc. of water at room temperature, whereby a yellow precipitate was formed. The aqueous mixture was allowed to stand for a while, was then vacuum-filtered, and the filter cake was washed with water and then dried. 9.2 gm. (90% of theory) of raw reaction product Was obtained, which was re-precipitated from 0.1 N hydrochloric acid with 2 N ammonia and then recrystallized once from a mixture of methanol and water (3:1) and once from a mixture of equal parts by volume of benzene and cyclohexane. The purified product had a melting point of 176-178 C. and Was identified to be 2-diisopropanolamino-4,7-dimorpholino-6-phenyl-pteridine of the formula theory.

EXAMPLE 3 Preparation of 2-diisopropanolamino-4,7-dimorpholino-6- phenyl-pteridine by Method B 4.2 gm. (0.01 mol) of 2-methylthio-4,7-dimorpholino- 6-phenyl-pteridine, M.P. 255257 C. (obtained by refluxing 4,7 dichloro-2-methylthio-6-phenyl-pteridine with morpholine for about one hour), were admixed with 20 gm. of diisopropanolamine and a small amount of copper sulfate, and the mixture was heated at 190200 C. for about two hours. Thereafter, the dark-colored reaction solution was poured into about 400 cc. of water at room temperature, whereby an-orange precipitate was formed which was immediately collected and reprecipitated from 0.1 N hydrocholoric acid with 2 N ammonia, yielding 2.6 gm. (51% of theory) of the raw reaction product. The raw product was recrystallized once from a mixture of methanol and water (3:1 by volume) and once from a mixture of equal volumes of benzene and cyclohexane. The purified product had a melting point of 175l78 C. and was identified to be 2-diisopropanolamino-4,7-dimorpholino-6-phenyl-pteridine.

EXAMPLE 4 4.3 gm. (0.01 mol) of 4-ethylthio-7-chloro-2-diisopropanolamino-6-phenyl-pteridine, M.P. l66-167 C. (obtained by heating 4-ethylthio-2,7-dichloro 6 phenylpteridine with diisopropanolamine in dioxane for five hours at 60 C.), admixed with 30 cc. of morpholine and and a small amount of morpholine hydrochloride, and the mixture Was heated for fifteen hours at about C. in a closed pressure tube. Thereafter, the excess unreacted morpholine was distilled off in vacuo, and the residue was taken up in about 400 cc. of water at room temperature, whereby a preciptate was formed. The precipitate was collected, reprecipitated once from 0.1 N hydrochloric acid with 2 N ammonia, and recrystallized once from a mixture of methanol and water (4:1 by volume) and once from a mixture of equal parts by volume of benzene and cyclohexane, yielding 1.8 gm. (35% of theory) of 2- diisopropanolamino-4,7-dimorpholino 6 phenyl-pteridine, which was identical to the end product of Example 3.

EXAMPLE 5 Using a procedure analogous to that described in Example 4, 2-diisopropanolamino 4,7-dimorpholino-6-phenylpteridine was also prepared from 4.8 gm. (0.01 mol) of 4 ethylthio-2-diisopropanolamino-7-morpholino-6-phenyl-pteridine, M.P. 202-204 C. (obtained by refluxing 4- ethylthio-7-chloro-2 diisopropanolamino-6-phenyl-pteridine with morpholine in dioxane for one hour), and morpholine.

EXAMPLE 6 5.2 gm. (0.01 mol) of 2-diisopropanolamino-4morpholino-7-phenoxy-6-phenyl-pteridine, M.P. 215-216 C. (obtained by heating 7-chloro-2-diisopropanolamino-4-morpholino-6-phenyl-pteridine with sodium phenolate in phenol), were admixed with 50 cc. of morpholine and 1 gm. of morpholine hydrochloride, and the mixture was refluxed for twelve hours. Thereafter, the reaction solution was evaporated to about one-half its volume and was then poured into about 300 cc. of water; a yellow amorphous precipitate was formed, which was collected by vacuum filtration, washed with water and dried, yielding 3.9 gm. (76% of theory) of raw reaction product. For purification purposes the raw product was reprecipitated once from 0.1 N hydrochloric acid with 2 N ammonia and recrystallized once from a mixture of methanol and water (3:1 by volume) and once from a mixture of equal volumes of benzene and cyclohexane. The purified product had a melting point of 178 C. and was identified to be 2-diisopropanolamino-4,7-dimorpholino-6pheny1-pteridine.

EXAMPLE 7 Using a procedure analogous to that described in Example 6, 2-diisopropanolamino-4-morpholino-7-pyrrolidino- 6-phenyl-pteridine, M.P. 195197 C., was prepared by heating 2-diisopropanolamino-4-morpholino-7-phenoxy-6- phenyl (M.P. 215-215 C.) with pyrrolidine at about 120 C. for twelve hours in a closed pressure tube. The yield was 73% of theory.

EXAMPLE 8 Using a procedure analogous to that described in Example '1, 2-diisopropanolamino-7-(2'-methylmorpholino)-4- morpholino-6-phenyl-pteridine, M.P. 189-191 C., of the formula was prepared from 7-chloro-2-diisopropanolamino-4-morpholino-6-phenyl-pteridine (M.P. 177179 C.) and 2- methyl-morpholine.

EXAMPLE 9 Using a procedure analogous to that described in Example 1, 2-diisopropanolamino-4-(2'-methyl-morpholino)-7- morpholino-6phenyl-pteridine, M.P. 87-95 C., was prepared from 7-chloro-2-diisopropanolamino-4-(2-methylmorpholino)-6-phenyl-pteridine (M.P. 97103 C.) and morpholine.

EXAMPLE 10 Using a procedure analogous to that described in Example 1, 2-diisopropanolamino-4,7-di(2'-methyl-morpholino)-6-phenyl-pteridine, M.P. 100140 C., was prepared from 7 chloro-2-diisopropanolamino-4-(2'-methyl-morpholino)-6-phenyl-pteridine and Z-methyl-morpholine.

EXAMPLE 1 1 Using a procedure analogous to that described in Example 1, 2-(N-ethanol-isopropanolamino)-4-(2'-methyl-morpholino) -7-morpholino-6-phenyl-pteridine, M.P. 1 10-120 C., of the formula was prepared from 7-chloro-2-(N-ethanol-isopropanolamino) 4 (2' methyl morpholino) 6 phenyl-pteridine (M.P. 95-98 C.) and morpholine.

EXAMPLE 12 C., was prepared from 7-chloro-2-(N-ethanol-isoropanolamino)-4-(2-methyl-morpholino)-6-pheny1-pteridine and pyrrolidine.

EXAMPLE 14 Using a procedure analogous to that described in Example 1, 2-diisopropanolamino-4- 2'-methyl-morpholino -7- (3'-hydroxy-'piperidino) 6 phenyl pteridine, M.P. 95 120 C., of the formula was prepared from 7-chl0ro-2-diisopropanolamino-4-(2- methyl-morpholino)-6-phenyl-pteri-dine and 3-hydroxypiperidine.

EXAMPLE 15 Using a procedure analogous to that described in Example 1, 2-diisopropanolamino-4-(2'-methyl-morpholino)-7- piperidino-6-phenyl-pteridine, M.P. 110 C., was prepared from 7-chloro-2-diisopropanolamino-4-(2-methylmorpholino)-6-phenyl-pteridine and piperidine.

EXAMPLE 16 Using a procedure analogous to that described in Example 1, 2-diisopropanolamino-4-(2'-methyl-morpholino)-7- pyrrolidinO-G- phenyI-pteridine, M.P. 75-105 C., was prepared from 7-chloro-2-diisopropanolamino-4-(2'-methylmorpholino)-6-phenyl-pteridine and pyrrolidine.

EXAMPLE 17 Using a procedure analogous to that described in Example 1, Z-(N-ethanol-ethylamino) 4,7 dimorpholino 6- phenyl-pteridine, M.P. -110 C., was prepared from 7- chloro-2-(N-ethanol-ethylamino)-4-morpholino-6-phenylpteridine (M.P. 143148 C.) and morpholine.

The compounds according to the present invention, that is, those embraced by formula I above, have useful pharmacodynamic properties. More particularly, they exhibit very strong, long-lasting coronary-dilating activities, coupled with very low toxicity in warm blooded animals, such as dogs. Particularly active in this respect are the following:

(A) 2-diisopropanolamino-4-(2-methyl-morpholino)-7- morpholino-6-phenyl-pteridine; and

(B) Z-diisopropanolamino-4,7-di(2' methylmorpholino)-6-pheny1-pteridine.

These two compounds, that is compounds A and B, were pharmacologically tested for coronary-dilating activity in comparison with a known, very effective coronary dilator, namely, 2,6-bis-diethanolamino-4,S-dipiperidinoyrimido [5,4-d]pyrimidine (compound C), in dogs under chloraloseurethane anaesthesia with open thorax. The coronary blood flow rate was measured with the aid of an electromagnetic fiowmeter 'before, during and after the intravenous administration of 0.05 to 0.1 mgm./kg. of each compound. At the same time, the blood flow rate in the hind legs, the blood pressure and the heart beat frequency were continuously measured. Each compound was tested on from 3 to 4 dogs.

The relative coronary-dilating effectiveness of compounds A and B in relation to that of compound C was determined by planimetric evaluation of the coronary blood flow curve, taking into consideration the effective strength and duration of effective action.

In addition, the median lethal dose (LD of the compounds in question was determined by standard pharamacological methods in mice.

7 The following table shows the results obtained from these tests:

TABLE I Relative Duration Blood pressure effective of Dose Number coronaryeffective Duration LD mgm./kg. ol' dilating action in Decrease, in mgm./kg. i.v. animals activity minutes mm. Hg minutes i.v.

Compound:

These results clearly show that the compounds according to the instant invention exhibit very strong and longlasting coronary-dilating activities, as well as weak hypertensive activities of long duration. The peripheral blood flow was not significantly affected by compounds A and B, and their diminishing effect upon the cardiac frequency was minor at the indicated dose.

For pharmaceutical purposes the compounds of the present invention are administered to warm blooded animals in need of coronary-dilating treatment perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective coronary-dilating dosage unit of the compounds of the instant invention is from 0.083 to 3.4 mgm./ kg. body weight, preferably from 0.165 to 1.7 mgm./kg. body weight.

The following examples illustrate a few dosage unit compositions comprising a compound according to the present invention as an active ingredient and represent the best mode contemplated of putting the invention to practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 18 Intravenous solution The solution was compounded from the following ingredients:

1 By vol.

Compounding procedure The polyethyleneglycol was admixed with an equal volume of distilled water, the mixture was heated to 80 C., and the tartaric acid as well as the pteridine compound were dissolved therein. The resulting solution was cooled to room temperature, diluted to the indicated volume with additional distilled water and then filtered until free from suspended particles. The filtrate was filled into 2 cc. white ampules, which were then sterilized for 20 minutes at 120 C. and sealed. One ampule contained 10 mgm. of the pteridine compound, and when the contents thereof were administered by intravenous injection to a warm-blooded animal of about 60 kg. body weight in need of such treatment, very good coronary-dilating effects of long duration were produced.

EXAMPLE l9 Coated pills The pill core composition was compounded from the following ingredients:

Parts Z-diisopropanolamino-4,7-dimorpholino-6- phenyl-pteridine 30.0 Lactose 30.0 Potato starch 16.5 Polyvinylpyrrolidone 3.0 Magnesium stearate 0.5

Total 80.0

Compounding procedure The pteridine compound was intimately admixed with the lactose and the potato starch, the mixture was moistened with an ethanolic 25% solution of the polyvinylpyrrolidone, the moist mass was forced through a 1.5 mm.- mesh screen, and the granulate obtained thereby was dried at C. and was again passed through a 1 mm.-mesh screen. The dry granulate was then admixed with the magnesium stearate, and the mixture was pressed into 80 mgm. pill cores with the aid of a conventional tabletmaking machine. The pill cores were then coated in conventional manner with a thin shell consisting essentially of sugar and talcum. One coated pill contained 30 mgm. of the pteridine compound and, when administered perorally to a warm-blooded animal of about kg. weight in need of such treatment, produced very 'good and long-lasting coronary-dilating effects.

EXAMPLE 20 Tablets The tablet composition was compounded from the following ingredients:

Parts 2-diisopropanolamino-4,7-dimorpholino-6- phenyl-pteridine 60.0 Lactose 30.0 Potato starch 23.00

Polyvinylpyrrolidone 6.0 Magnesium stearate 1.0

Total 120.0

Compounding procedure The pteridine compound, the lactose and thepotato starch were intimately admixed with each other, the mixture was moistened with an ethanolic 25% solution of the polyvinylpyrrolidone, the moist mass was forced through a 1.5 nmL-mesh screen, and the moist granulate obtained thereby was dried at 45 C. and was again passed through a 1 mm.-mesh screen. The dry granulate was admixed with the magnesium stearate, and the mixture was pressed into 120 mgm. tablets with the aid of a conventional tablet-making machine. One tablet contained 60 mgm. of the pteridine compound and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good and long-lasting coronary-dilating effects.

EXAMPLE 21 Gelatin capsules The capsule filler composition was compounded from the following ingredients:

Parts 2-diisopropanolamino-4,7-dimorpholino-6- phenyl-pteridine 50.0 Lactose 60.0 Talcum 10.0

Total 120.0

By vol.

Compounding procedure The pteridine compound was intimately admixed with the lactose and the talcum, and 12 mgm.-portions of the mixture were filled into gelatin capsules of suitable size. One capsule contained 50 mgm. of the pteridine compound and, when administered perorally to a warmblooded animal of about 60 kg. body weight in need of such treatment, produced very good and long-lasting coronary-dilating effects.

EXAMPLE 22 Drop solution The solution was compounded from the following ingredients: 1

Parts 2-diisopropanolamino-4,7-dimorpholino-6- phenyl-pteridine 20.0 Tartaric acid 5.0 Cane sugar 300.0 Sorbic acid 1.0 Flavoring 40.0 Ethanol 1 200.0 Polyethyleneglycol 600 1 200.0 Demineralized water, q.s.ad 1000.0

1 By v01.

Compounding procedure The sorbic acid was dissolved in the ethanol, an equal volume of demineralized water was added to the solution, and the pteridine compound and the tartaric acid were dissolved therein while stirring (solution A). The cane sugar was dissolved in the remaining amount of demineralized water (solution B). Solution B, the polyethylene glycol and the flavoring were added to solution A while stirring, and the finished solution was filtered until clear.- 1 cc. of the drop solution (about 5 drops) contained 20 mgm. of the pteridine compound and, when administered perorally to a warm-blooded animal of about 60 kgj'body weight in need of such treatment, produced very good and long-lasting coronary-dilating effects.

EXAMPLE 23 Suppositories The suppository composition was compounded from the following ingredients:

Compounding procedure The finely pulverized pteridine compound was stirred with the aid of an immersion homogenizer into the cocoa butter which had previously been melted and then cooled to 40 C. The resulting mixture was then poured at about 35 C. into cooled suppository molds, each holding 1700 mgm. of the mixture. One suppository contained mgm. of the pteridine compound and, when administered by the rectal route to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very good and long-lasting coronary-dilating effects.

Although the above dosage unit composition examples illustrate only one compound of the present invention as an active ingredient, it should be understood and will be obvious to others skilled in the art that any other compound embraced by Formula I may be substituted for the particular pteridine compound in Examples 18 through 23. Moreover, the amount of pteridine compound in these examples may be varied pursuant to the body weight of the host to achieve the unit dosage range set forth above, and the amounts and nature of the inert carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments, it will be readily apparent to those skilled in the art that my invention is not limited to those embodiments and that various other changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

I claim:

1. A compound of the formula wherein R is morpholino or 2'-methyl-morpholino, R is pyrrolidino, piperidino, 3-hydroxy-piperidino,

morpholino, or 2-methyl-morpholino, and R is fi-hydroxy-ethyl or fi-hydroxy-n-propyl.

2. A compound according to claim 1, which is Z-[di-(B- hydroxy-n-propyl)-amino]-4-(2-methyl-morpholino) 6- phenyl-7-morpholino-pteridine.

3. A compound according to claim 1, which is Z-[di-(fihydroxy-n-propyl) -amino]-4,7-di-(2'-methy1 piperidino)- 6-phenyl-pteridine.

4. A compound according to claim 1, which is Z-[di-(B- hydroxyl-n-propyl)-amino]-4,7-dimorpholino 6 phenylpteridine.

5. A compound according to claim 1, which is 2-[di-(flhydroxy-n-propyl)-amino]-4-(2'-methyl-morpholino) 6- phenyl-7-pyrrolidino-pteridine.

6. A compound according to claim 1, which is 2-[N- (fi-hydroxyethyl)-N-(/3-hydroxy-n-propyl)-amino]-4 (2'- methyl-morpholino) -6-phenyl-7-morpholino-pteridine.

7. A compound according to claim 1, which is Z-[N-(fihydroxy-ethyD-N-(fl-hydroxy-n-propyl)-amin0]-4,7 di- (2-methyl-morpholino) -6-phenyl-p teridine.

8. A compound according to claim 1, which is Z-[di-(flhydroxy-n-propyl)-amino]-4-(2-methyl-morpholino) 6- phenyl-7- (3 -hydroxy-piperidino -pteridine.

5%? UNITED STATES PATENT OF TICE CERTIFICATE OF CORRECTION Patent No. 1 106 Dated January 9: 97

Inventor (K) Josef ROCh It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 1, line 22: correct the formula to read cH -gH -CH: N 3

Col. 1, line 27: insert a comma after "3 '-hydroxy-p1per1dino" C01. 5, line a: (M.P. 215-215c.) should read-{H.P. 215-216 Col. 9, line 22-: erase By vol.

Signed and sealed this 29th day of June 1 971 EAL) Attest:

EDWARD M.FLETCHER,J'R. WILLIAM E. somm Attesting Officer Commissioner 01' Pa 

